6-Acylamino-penam-3-carboxylic and 7-acylamino-3-cephem-4-carboxylic acids

ABSTRACT

6-Acylamino-penam-3-carboxylic acids and 7-acylamino-3-cephem-4-carboxylic acids in which the acyl group has the formula ##STR1## IN WHICH R 1  is hydrogen, R 2  is optionally substituted phenyl, thienyl or furyl or R 1  and R 2  together are optionally substituted cycloalkyl, n and m independently of one another represent 0 or 1 and B represents an optionally substituted 2,6-dioxo- or 2,6-dithioxo-1,2,3,6-tetrahydro-pyrimidyl, 2-thioxo-6-oxo-1,2,3,6-tetrahydropyrimidyl, 2,6-dihydroxy- or 2,6-dimercapto-pyrimidyl, 2-mercapto-6-hydroxy-pyrimidyl, 2,6-diaminopyrimidyl, 2-amino-6-hydroxy-pyrimidyl or 2,6-dihalogenopyrimidyl radical, these radicals being bonded in the 4- or 5-position.

The invention relates to new therapeutically valuable derivatives of6-amino-2,2-dimethyl-penam-3-carboxylic acid and of7-amino-ceph-3-em-4-carboxylic acid and their salts, processes for theirmanufacture and pharmaceutical preparations which contain the newcompounds.

The new compounds have the general formula I ##STR2## wherein thegrouping -S-A- represents a radical of the formula Ia or Ib ##STR3##wherein R₃ denotes a free or therapeutically usable esterified carboxylgroup and R₄ represents hydrogen, lower alkoxy or an optionallysubstituted methyl group and wherein, if the radicals R₁ and R₂ areseparate, R₁ is hydrogen and R₂ is optionally substituted phenyl,thienyl or furyl and, if the radicals R₁ and R₂ are linked, they form,together with the carbon atom, an optionally substituted cycloalkyl ringwith 4 to 7 carbon atoms, and wherein n and m independently of oneanother represent 0 or 1 and B represents an optionally substituted2,6-dioxo- or 2,6-dithioxo-1,2,3,6-tetrahydropyrimidyl,2-thioxo-6-oxo-1,2,3,6-tetrahydropyrimidyl, 2,6-dihydroxy- or2,6-dimercapto-pyrimidyl, 2-mercapto-6-hydroxypyrimidyl,2,6-diaminopyrimidyl, 2-amino-6-hydroxy-pyrimidyl or2,6-dihalogenopyrimidyl radical, these radicals being bonded in the 4-or 5-position.

Preferably, n represents 1 and m represents 0. Substituents of theabovementioned cyclic radicals R₂ or R₁ + R₂ are, for example, loweralkyl, such as methyl, lower alkoxy, such as methoxy, halogen atoms, forexample fluorine or chlorine, trifluoromethyl, the nitro group and aboveall carbamoyl and acyl, especially lower alkanoyl, such as acetyl. Thecyclic radicals are preferably unsubstituted. R₁ + R₂ represent,together with the carbon atom, above all cyclopentyl, cyclohexyl orcyclohexenyl. If R₂ represents thienyl or furyl, these radicals arebonded in the 2- or 3-position, preferably in the 2-position.

Above all, R₁ represents hydrogen and R₂ represents unsubstitutedphenyl.

The following general formulae ##STR4## can be written for the radicalB; in these, X₁ represents oxygen or sulphur and X₂ represents oxygenor, if X₁ represents sulphur, X₂ can also denote sulphur. Preferably, X₁and X₂ represent oxygen. The substitutent R₅ can be in the 5- or4-position depending on whether the radical B is bonded in the 4- or5-position.

R₅ represents hydrogen, halogen, especially chlorine or fluorine, or anoptionally substituted aliphatic or aromatic hydrocarbon radical.

An optionally substituted aliphatic hydrocarbon radical R₅ is above alla lower alkyl radical, especially a radical with 1-4carbon atoms such asmethyl, ethyl, propyl, isopropyl, n-butyl or tert.butyl. The radical canbe substituted by one or more substituents. As substituents there shouldin particular be mentioned free, esterified or etherified hydroxyl ormercapto groups, such as halogen, acyloxy, above all lower alkanoyloxy,such as acetoxy, or aroyloxy, such as benzoyloxy, lower alkoxy, such asmethoxy, aryloxy, such as phenoxy which is optionally substituted, inparticular by halogen, nitro, lower alkyl or lower alkoxy, for examplep-chlorophenoxy, or lower alkylmercapto, such as methylmercapto.

An optionally substituted aromatic hydrocarbon radical R₅ is amonocyclic or bicyclic radical, for example naphthyl or preferablyphenyl. These radicals can be substituted in the same manner as thealiphatic radicals or can be substituted by lower alkyl. Examples whichshould be mentioned are p-nitrophenyl or m-methoxyphenyl.

R₅ above all represents hydrogen.

R₆ and R₇ independently of one another represent hydrogen, or anoptionally substituted aliphatic hydrocarbon radical. These hydrocarbonradicals and their substituents are the same as indicated above for thecorresponding radicals R₅. Preferably, R₆ and R₇ denote hydrogen and/orlower alkyl with 1-4 carbon atoms such as ethyl, propyl, isopropyl ortert, butyl, but especially methyl. Above all, R₆ and R₇ both representhydrogen.

R₈ and R₉ also independently of one another represent hydrogen or anoptionally substituted aliphatic hydrocarbon radical, with thehydrocarbon radicals and the substituents having the same meaning asindicated above for corresponding R₅ radicals. Preferably, R₈ and R₉both represent hydrogen.

R₁₀, R₁₁, R₁₂ and R₁₃ independently of one another represent hydrogen oran organic radical having the meaning of R₈ and R₉.

In the formula B₅, Hal represents a halogen atom, especially fluorineand above all chlorine.

The substituent R₃ present in the penicillanic acid and cephalosporanicacid derivatives of the formula Ia and Ib is, as mentioned, a free ortherapeutically usable esterified carboxyl group, for example an estergroup which can be split enzymatically.

Esters which can be split enzymatically are above all those whichcontain an ester group which can be split under physiologicalconditions. These esters can readily be resorbed in the organism and aretherefore therapeutically usable as such. Esters of this nature aredescribed, for example, in British Patent Specification No. 1,229,453,in Belgian Pat. No. 789,821 and in German Offenlegungsschrift DT1,951,012, DT 2,228,012 and DT 2,230,620. Such esters are derived, forexample, from 5-hydroxyindanol or 3,4-benzo-5-oxo-tetrahydro-2-furanolor from alcohols of the formula HO--CH₂ OCO--R₃ ", wherein R₃ " canrepresent an alkyl radical or an aminoalkyl radical or a cycloalkylradical with 3-7carbon atoms. In particular, R₃ " denotes a lower alkylradical, such as methyl, ethyl, or isopropyl but above all tert.-butyl,an α-amino-lower alkyl radical, such as 1-amino-2-methylpropyl or1-amino-3-methylbutyl, a cyclopentyl radical or cyclohexyl radical.

The radical R₄ in the cephalosporanic acid derivatives of the formula Ibrepresents, as mentioned, a hydrogen atom, (in which case the side chainin the 3-position of cephalosporin C is absent), lower alkoxy,especially methoxy (compare U.S. Patent application, Ser. No. 373,818)or an unsubstituted or substituted methyl group. Substituents of themethyl group are, above all, a free, esterified or etherified hydroxylor mercapto group, an optionally N-substituted carbamoyloxy orthiocarbamoylmercapto group, or above all a quaternary ammonium group,and also the nitrile group,

An esterified hydroxyl or mercapto group contains, as the acid radical,above all the radical of a carboxylic acid or thiocarboxylic acid, forexample lower alkanoyl which is optionally substituted by halogen atoms,especially chlorine, such as formyl, propionyl, butyryl, pivaloyl,chloroacetyl, but especialy acetyl, or aroyl or aryl-lower alkanoylwhich are optionally substituted, for example by lower alkyl, loweralkoxy, halogen or nitro, for example benzoyl or phenylacetyl, and also,as a thiocarboxylic acid radical, in particular aroylthio which isoptionally substituted as mentioned, above all benzoylthio.Additionally, hydroxyl groups esterified by hydrogen halide acids shouldbe mentioned; the methyl group R₄ can therefore be substituted by, forexample, fluorine, chlorine or bromine.

Examples of etherified hydroxyl groups are described in Belgian Pat. No.719,710. Lower alkoxy, such as methoxy, ethoxy or n-propoxy, should besingled out.

Etherified mercapto groups contain, as etherifying radicals, forexample, lower alkyl, for example methyl, and also optionallysubstituted phenyl or heterocyclyl. Phenyl can be substituted, by, forexample, lower alkyl, lower alkoxy, halogen or nitro. The heterocyclylradicals preferably possess 5-6 ring atoms and contain, as hetero-atoms,nitrogen which is optionally in the N-oxidised form, and/or oxygen orsulphur. Examples to be mentioned are 1-oxidised 2-pyrimidyl,pyridazinyl, pyrazinyl, imidazolyl, imidazolidyl and purinyl. Theseradicals can be substituted, for example by lower alkyl, lower alkoxy,hydroxyl or halogen. Optionally substituted heterocyclyl radicals ofaromatic character with 5 ring atoms, which contain 2 nitrogen atoms andat least one further hetero-atom from the group of nitrogen, oxygen andsulphur, should be singled out particularly. Preferred substituents arelower alkyl radicals with 1-5 carbon atoms, such as methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl or tert.butyl, lower alkoxy orlower alkylthio radicals with 1-5 carbon atoms, especially methylthio,cycloalkyl radicals such as cyclopentyl or cyclohexyl, or aryl radicalssuch as phenyl or substituted phenyl, for example phenyl substituted byone or more nitro groups or halogen atoms or lower alkyl or lower alkoxygroups, or unsubstituted or substituted thienyl, especially thienyl-(2)or thienyl substituted as indicated for phenyl, or optionallymonosubstituted or disubstituted amino groups, for example acetylamino,tert.butoxycarbonylamino, tert. amyloxycarbonylamino or sulphonylamino.

As examples of the heterocyclyl radical there should be mentioned:1H-1,2,3,Triazol-5-yl, 1,3,4-triazol-2-yl, 5-methyl-1,3,4-triazol-2-yl,1H-1,2,4-triazol-5-yl, 1-phenyl-3-methyl-1H-1,2,4-triazol-5-yl,4,5-dimethyl-4H-1,2,4-triazol-3-yl, 4-phenyl-4H-1,2,4-triazol-3-yl,1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-ethyl-1H-tetrazol-5-yl,1-n-propyl-1H-tetrazol-5-yl, 1-isopropyl-1H-tetrazol-5-yl,1-n-butyl-1H-tetrazol-5-yl, 1-cyclopentyl-1H-tetrazol-5-yl,1-phenyl-1H-tetrazol-5-yl, 1-p-chlorophenyl-1H-tetrazol-5-yl,1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl,2-methyl-1,3,4-thiadiazol-5-yl, 2-methylthio-1,3,4-thiadiazol-5-yl,2-ethyl-1,3,4-thiadiazol-5-yl, 2-n-propyl-1,3,4-thiadiazol-5-yl,2-isopropyl-1,3,4-thiadiazol-5-yl, 2-phenyl-1,3,4-thiadiazol-5-yl,1,2,4-oxadiazol-5-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-5-yl,2-methyl-1,3,4-oxadiazol-5-yl, 2-ethyl-1,3,4-oxadiazol-5-yl,2-phenyl-1,3,4-oxadiazol-5-yl, 2-p-nitrophenyl-1,3,4-oxadiazol-5-yl,2-[thienyl(2)]-1,3,4-oxadiazol-5-yl and thiatriazol-5-yl.

An optionally N-substituted carbamoyloxy group or thiocarbamoylmercaptogroup is, for example, a group of the formula --O--CO--NH--R₁₇ (FrenchPat. No. 1,463,831) or ##STR5## wherein R₁₇ is an optionallyhalogen-substituted lower alkyl radical and R₁₈ is hydrogen or R₁₇(compare J. Med. Chem. 8, 174 (1965). Above all, R₁₇ is methyl, ethyl orchlorine-substituted methyl or ethyl, especially β-chloroethyl,

In a quaternary ammonium-methyl group R₄, the ammonium part ispreferably an unsubstituted or substituted pyridinium group, especiallyan unsubstituted pyridinium group.

Examples of substituents of the pyridinium group which should bementioned are those listed in Antimicrobial Agents and Chemotherapy1966, pages 573-580, such as unsubstituted or substituted, for examplehydroxy-substituted or carboxy-substituted, lower alkyl, for examplemethyl, ethyl, propyl, hydroxymethyl or carboxymethyl, halogen, such asfluorine, chlorine, bromine or iodine, or trifluoromethyl, hydroxyl,sulpho, carboxyl, nitrile, lower alkoxycarbonyl, such as methoxycarbonylor ethoxycarbonyl, lower alkylcarbonyl, such as methylcarbonyl, andespecially unsubstituted or substituted carbamoyl, for example carbamoylsubstituted by lower alkyl, hydroxy-lower alkyl or halogeno-lower alkyl,especially chlorolower alkyl, such as N-methylcarbamoyl,N-isopropylcarbamoyl, N-β-chloroethylcarbamoyl and above all carbamoyl.The substituents can be in the 2-, 3- and/or 4-position, and arepreferably in the 3- or 4-position.

Salts of compounds of the present invention are above allpharmaceutically usable, non-toxic salts of compounds which are capableof forming salts with bases. Such salts are above all metal salts orammonium salts, such as alkali metal salts, alkaline earth metal saltsand earth metal salts, for example sodium, potassium, magnesium, calciumor aluminium salts, and also ammonium salts with ammonia or suitableorganic amines; above all, it is possible to use for salt formationaliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphaticprimary, secondary or tertiary monoamines, diamines or polyamines aswell as heterocyclic bases, such as lower alkylamines, for exampletriethylamine, hydroxy-lower alkylamines, for example2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine, basic aminoacids such as lysine, ornithineor arginine, basic aliphatic esters of carboxylic acids, for example4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, forexample 1-ethylpiperidine, cycloalkylamines, for examplebicyclohexylamine, or benzylamines, for exampleN,N'-dibenzyl-ethylenediamine and also bases of the pyridine type, forexample pyridine, collidine or quinoline.

The new compounds can be in the form of mixtures of isomers, for exampleracemates, or of individual isomers, for example optically activeantipodes.

The new compounds of the formula I display a pharmacological action,especially a particularly pronounced antibacterial action. Thus they areactive against Gram-positive bacteria, such as Staphylococcus aureus,but above all against Gram-negative bacteria, for example Escheria coli,Klebsiella pneumonia and Salmonella typhosa, and especially againstBacterium proteus and Pseudomonas aeruginosa. Thus they inhibit thegrowth of Pseudomonas aeruginosa at dilutions down to 0.4 γ/ml. They cantherefore be used for combating infections which are caused by suchmicro-organisms and can also be used as fodder additives, for thepreservation of foodstuffs or as disinfectants.

Compounds to be singled out are 3-cephem compounds of the formula##STR6## and especially penam compounds of the formula ##STR7## whereinR₃ ' represents hydroxyl and R₄ ' represents hydrogen, methyl, methoxy,lower alkanoyloxymethyl, for example acetoxymethyl, or pyridiniummethyl,1-oxidised 2-pyridylthiomethyl, 1,3,4-thiadiazol-2-ylthiomethyl,2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl,3-methyl-1,2,4-thiadiazol-5-ylthiomethyl or1-methyl-5-tetrazolylthiomethyl which are optionally substituted bylower alkyl, hydroxyl, halogen, carboxyl or above all carbamoyl, andwherein n represents 0 or 1 and B' represents a radical of the formulaB₁ bonded in the 4- or 5-position, in which radical R₆ and R₇ denotehydrogen and R₅ denotes lower alkyl, halogen, phenyl or above allhydrogen.

Compounds which are therapeutically particularly valuable are penamcompounds of the formula IB, wherein B' has the indicated meaning and R₃' represents hydroxyl, such as6-[D(-)-α-(1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)phenylacetamido]-penicillanicacid and6[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid and corresponding cephalosporanic acid compounds and non-toxicsalts, such as alkali metal salts, for example sodium salts, or alkalineearth metal salts, such as calcium salts, of these compounds, and alsocephem compounds of the formula IA, wherein B' has the indicatedmeaning, R₃ represents hydroxyl and R₄ ' represents pyridiniummethyl,such as7-[D(-)-α-(1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-pyridiniummethyl-4-carboxylicacid,7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-3-pyridiniummethyl-4-carboxylicacid and7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-3-[1-carbamoyl-pyridiniomethyl)]-ceph-3-em-4-carboxylicacid and their salts.

The new compounds are manufactured according to methods which are inthemselves known. Thus they are obtained when a compound of the formulaII ##STR8## wherein R₁, R₂, A and n have the indicated meaning andwherein a free carboxyl group R₃ which may be present in the radical Ais optionally protected, or a salt thereof, is acylated with the acid ofthe formula III

    b -- (ch.sub.2).sub.m --COOH                               III,

wherein B and m have the indicated meaning, or with a reactivederivative of this acid. The compounds of the formula II, wherein nrepresents 1, can also be obtained by acylation of the compound II'##STR9## wherein A has the indicated meaning and wherein a free carboxylgroup R₃ which may be present in the radical A is optionally protected,or of a salt thereof, with the acid of the formula III' ##STR10##wherein R₁, R₂, B and m have the indicated meaning, or with a reactivederivative of this acid. If a protective group is present in a compoundof the formula Ia or Ib obtained according to one of the two processes,it can be split off in a known manner. If desired, a free carboxyl groupR₃ present in a product of the formula Ia or Ib can be converted into atherapeutically usable ester group R₃ and/or, if desired, an optionallysubstituted methyl group R₄ can be converted into another group R₄and/or, if desired, a compound obtained as the free acid can beconverted into a salt or a salt obtained can be converted into the freeacid and/or an isomer mixture obtained can be separated into theindividual isomers.

A free carboxyl group R₃ in a starting material of the formula II or II'can in particular be protected by esterification. The ester groups usedare in particular those which can be split to the free carboxyl group inan acid or weakly alkaline medium, solvolytically, for example byhydrolysis or alcoholysis, hydrolytically, reductively or bynucleophilic exchange.

Ester groups which can easily be split by solvolysis with a solventcontaining hydroxyl groups, for example water or alcohols such as, forexample, methanol or ethanol, preferably under neutral conditions, areabove all those which are derived from silyl alcohol or stannyl alcohol.Such groups are described, for example, in British Patent SpecificationsNos. 1,073,530 and 1,211,694, and in German Offenlegungsschrift1,800,698.

Esters which are easily split in an acid medium, for example in thepresence of hydrogen chloride, hydrogen fluoride or hydrogen bromide orin the presence of organic acids such as acetic acid, trifluoroaceticacid, formic acid or their mixtures with water are above all esterswhich are derived from lower alkanols which are poly-branched in theα-position or from lower alkanols which contain one or more electrondonors in the α-position. Examples of such ester groups aretert.butoxycarbonyl, tert.amyloxycarbonyl, cyclopentyloxycarbonyl,cyclohexyloxycarbonyl, adamantyloxycarbonyl, furfuryloxycarbonyl,p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,diphenylmethoxycarbonyl and pivaloyloxymethoxycarbonyl. Ester groupswhich can be split by reduction, for example with zinc and acetic acid,are above all derived from 2-halogeno-lower alkanols, for example from2,2,2-trichloroethanol, 2-chloroethanol, 2-bromoethanol and2-iodoethanol.

Salts of starting substances of the formula II are especially those ofcompounds possessing a free carboxyl group, above all ammonium salts,such as tri-lower alkylammonium salts, for example triethylammoniumsalts, and also alkali metal salts.

The acylation of the compound II or II' with the acyl radical III orIII' is carried out according to methods which are in themselves known,especially in the manner known from peptide chemistry for the acylationof weakly basic amino groups. The acylating agent used which containsthe acyl radical III or III' is either the corresponding acid, in whichcase the reaction is carried out in the presence of a condensationagent, for example of a carbodiimide such as dicyclohexylcarbodiimide,or of Woodward Reagent K or L, or is a reactive acid derivative, aboveall an acid halide, especially an acid chloride or bromide, and also,for example, an acid azide, an activated ester or a mixed anhydride, forexample an anhydride with mono-esterified carbonic acid, such as acarbonic acid lower alkyl ester, for example carbonic acid methyl ester,or with an optionally halogen-substituted lower alkanoic acid such asformic acid or pivalic acid or trichloroacetic acid. Examples ofactivated esters are p-nitrophenyl esters, 2,4-dinitrophenyl esters,2,4,5- or 2,4,6-trichlorophenyl esters, pentachlorophenyl esters andalso, for example, the cyanomethyl ester, N-hydroxysuccinimide ester,N-hydroxypiperidine ester and N-hydroxyphthalimide ester.

The acylation reaction is carried out in the presence of a solvent ordiluent, if desired in the presence of a catalyst and/or in the presenceof basic agents such as aliphatic, aromatic or heterocyclic nitrogenbases, for example triethylamine, diisopropylethylamine,N,N-diethylaminoacetic acid ethyl ester, N-ethyl-morpholine,N,N-dimethylaniline, pyridine, 2-hydroxypyridine,p-dimethylaminopyridine, collidine or 2,6-lutidine.

The reaction is carried out at room temperture or with cooling orwarming, for example at temperatures of -70° to +100° C, optionally inan inert gas atmosphere, for example a nitrogen atmosphere, and/or withexclusion of moisture.

The acylating agents are known or can be manufactured in a manner whichis in itself known.

During the acylation reaction, it is desirable to protect free hydroxyl,mercapto, amino and/or carboxyl groups which may be present in thereactants, especially by easily removable protective groups, such as areknown, for example, from peptide synthesis, compare Schroder and Lubke"The Peptides", Vol. I. Academic Press, New York and London, 1965, andTh. Wieland, Angew, Chem. 63 (1951) 7-14, 66 (1954), 507-512, 69 (1957),362-372, 71 (1959), 417-425 and 75 (1963), 539-551. As examples of aminoprotective groups there should be mentioned optionally substitutedaralkyl groups, such as diphenylmethyl or triphenylmethyl groups, oracyl groups such as formyl, trifluoroacetyl, phthaloyl,p-toluenesulphonyl, benzylsulphonyl, benzenesulphenyl,o-nitrophenylsulphenyl or above all groups derived from carbonic acid orthiocarbonic acid, such as carbobenzoxy groups optionally substituted inthe aromatic radical by halogen atoms, nitro groups, lower alkyl orlower alkoxy or lower carbalkoxy groups, for example carbobenzoxy,p-bromocarbobenzoxy or p-chlorocarbobenzoxy, p-nitrocarbobenzoxy,p-methoxycarbobenzoxy, coloured benzyloxycarbonyl groups, such asp-phenylazo-benzyloxycarbonyl andp-(p'-methoxyphenylazo)-benzyloxycarbonyl, tolyloxycarbonyl,2-phenyl-isopropoxycarbonyl, 2-tolyl-isopropoxycarbonyl and above all2-(para-biphenyl)-2-propoxycarbonyl, and also aliphatic oxycarbonylgroups such as, for example, allyloxycarbonyl, cyclopentyloxycarbonyl,tert.amyloxycarbonyl, adamantyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl and above alltert.butoxycarbonyl, as well as, for example, carbamoyl, thiocarbamoyl,N-phenylcarbamoyl and N-phenylthiocarbamoyl. Easily removable estergroups for protecting a free carboxyl group have already been listedabove. Hydroxyl groups are preferably protected by etherification, forexample with tert.butanol. An example of a suitable mercapto protectivegroup is trityl.

In a compound of the formula I obtained according to the invention, aprotected carboxyl group R₃, especially an esterified carboxyl groupwhich can easily be converted into the free carboxyl group, can beconverted in the abovementioned manner into the free carboxyl group. Itis also possible, before splitting off the ester group, to convert theester group into a different ester group, for example to convert a2-bromoethyl ester group into a 2-iodoethyl ester group.

In compounds of the formula I, wherein the fragment -S-A- represents thegroup of the formula Ib, a radical R₄ can be converted into anothergroup of this type. Thus it is possible to treat a compound with anesterified hydroxymethyl radical R₄, wherein the esterified hydroxylgroup in particular denotes lower alkanoyloxy, for example acetoxy, withpyridine at elevated temperature, or first to react it with thiobenzoicacid and then to treat it with pyridine in the presence of a mercurysalt, or to react it with a suitable salt, such as potassiumthiocyanate, potassium iodide or potassium nitrate, and with pyridine inthe presence of water at a pH value of about 6.5 which is obtained, forexample, by means of phosphoric acid, and thus to obtain thecorresponding pyridiniummethyl compound which can, if necessary, beconverted into the inner salt (zwitter-ion form), for example bytreatment with a suitable ion exchange reagent. The pyridinium compoundcan also be manufactured according to the process of Belgian Pat. No.719,711, (DOS 1,795,643) by first converting the acetoxy group into agroup more suitable for nucleophilic replacement, for example a halogenatom or an acetoxy group possessing an electron-attracting substituent,such as, for example, chloroacetoxy, dichloroacetoxy or cyanoacetoxy.Furthermore it is possible to react compounds having a loweralkanoyloxymethyl group, for example an acetoxymethyl group, as theradical R₄, with a mercapto compound, such as an optionally substitutedlower alkylmercaptan, phenylmercaptan or heterocyclylmercaptan and thusto obtain compounds of the formula I, wherein R₄ in a partial formula Ibrepresents an etherified mercapto group.

Salts of compounds of the formula I can be manufactured in a mannerwhich is in itself known. Thus it is possible to form salts of compoundsof the formula I, wherein R₃ represents a free carboxyl group by, forexample, treatment with metal compounds, such as alkali metal salts ofsuitable carboxylic acids, for example the sodium salt ofα-ethyl-caproic acid, or with ammonia or a suitable organic amine.

Salts can be converted in the usual manner into the free compounds, inthe case of metal salts and ammonium salts by, for example, treatmentwith suitable acids or ion exchange exchangers.

Mixtures of isomers which are obtained can be separated into theindividual isomers according to methods which are in themselves known,for example by fractional crystallisation, absorption chromatography(column chromatography or thin layer chromatography) or other suitablemethods or separation. Resulting racemates can be separated into theantipodes in the usual manner, if appropriate after introducing ofsuitable salt-forming groups, for example by forming a mixture ofdiastereoisomeric salts with optically active salt-forming agents,separating the mixture into the diastereoisomeric salts and convertingthe separated salts into the free compounds, or by fractionalcrystallisation from optically active solvents.

The process also encompasses embodiments according to which compoundswhich arise as intermediate products are used as starting substances andthe remaining process steps are carried out with these, or the processis stopped at any stage; furthermore, starting substances can be used inthe form of derivatives or be formed during the reaction.

Preferably, such starting substances are used, and the reactionconditions are so chosen, as to give the compounds initially mentionedas being particularly preferred.

The starting substances of the formula II are known or can bemanufactured according to the processes already mentioned.

The new compounds can be used as medicines, for example in the form ofpharmaceutical preparations which contain an effective amount of theactive substance together with, or mixed with, inorganic or organic,solid or liquid, pharmaceutically usable excipients which are suitablefor enteral or, preferably, parenteral administration. Thus, tablets orgelatine capsules are used which contain the active compound togetherwith diluents, for example lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine, and lubricants, for example, silica,talc, stearic acid or salts thereof, such as magnesium stearate orcalcium stearate, and/or polyethylene glycol; tablets also containbinders, for example magnesium aluminium silicate, starches, such ascorn starch, wheat starch, rice starch or arrowroot, gelatine,tragacanth, methylcellulose sodium carboxymethylcellulose and/orpolyvinylpyrrolidone and, if desired, disintegrating agents, for examplestarches, agar, alginic acid or a salt thereof, such as sodium alginate,and/or effervescing mixtures, or adsorbents, dyestuffs, flavouringsubstances and sweeteners. Preferably, the pharmacologically activecompounds of the present invention are used in the form of injectablepreparations, for example of preparations which can be administeredintravenously, or of infusion solutions. Such solutions are preferablyisotonic aqueous solutions or suspensions, can these can be manufacturedbefore use, for example from lyophilised preparations which contain theactive substance by itself or together with an excipient, for examplemannitol. The pharmacological preparations can be sterilised and/orcontain auxiliaries, for example preservatives, stabilisers, wettingagents and/or emulsifiers, solubilising agents, salts for regulating theosmotic pressure and/or buffers. The present pharmaceutical preparationswhich can, if desired, contain further pharmacologically valuablesubstances, are prepared in a manner which is in itself known, forexample by means of conventional mixing, granulating, dragee-making,dissolving of lyophilising processes, and contain from about 0.1% to100%, and especially from about 1% to about 50%, of lyophilisates and upto 100% of the active substance.

In the context of the present description, organic radicals described as"lower" contain up to 6, preferably up to 4, carbon atoms; acyl radicalscontain up to 20, preferably up to 12, carbon atoms.

The examples which follow serve to illustrate the invention.

The following systems are used in thin layer chromatography:

System 52A n-butanol/glacial acetic acid/water (67:10:23)

System 67 n-butanol/ethanol/water (40:10:50, upper phase)

System 101 n-butanol/pyridine/glacial acetic acid/water (38:24:8:30)

System 101A n-butanol/pyridine/glacial acetic acid/water (42:24:4:30)

In the Examples the ED₅₀ means the concentration in mg/kg (mouse,subcutaneous, once on infection and once 3 hours later) at which 50 % ofthe animals infected with a lethal doses of Pseudomonas aeruginosa ATCC12055 survive.

EXAMPLE 1

A suspension of 4.38 g of anhydrous6-[D(-)-phenylglycylamino]-penicillanic acid in 120 ml of methylenechloride is treated with 2.60 ml of triethylamine whilst stirring andexcluding moisture and is then cooled to 0° C. A solution of 4.33 g oforotic acid chloride (manufactured according to the method of D. G.Crosby and R. V. Berthold, 7, Med. Chem. 6, 334 (1963) and freed fromunreacted orotic acid by dissolving in tetrahydrofurane) in 240 ml ofabsolute tetrahydrofurane is then added dropwise to the clear solutionat 0° C over the course of 20 minutes, whilst stirring and cooling in anice bath. The reaction mixture is stirred for 30 minutes at 0° C and 45minutes at room temperature. 300 ml of phosphate buffer solution of pH7.5 are then added, the solvent is evaporated off on a rotary evaporatorat 45° C and the phosphate buffer solution is twice extracted with ethylacetate. The clear aqueous phase is covered with ethyl acetate,acidified (pH 2.5) at 10° C by adding 20% strength phosphoric acidwhilst stirring and cooling with an ice bath, and exhaustively extractedwith ethyl acetate. The ethyl acetate extracts are combined, washed withsodium chloride solution and dried over sodium sulphate, and the solventis evaporated off on a rotary evaporator at 45° C. The product whichremains (3.70 g; 61% of theory) is crystallised from a mixture oftetrahydrofurane and ether.6-[D(-)-α-(1,2,3,6-Tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid melts, with decomposition, at 213°-215° C.

Thin layer chromatogram on silica gel: Rf_(52A) = 0.60, Rf₁₀₁ = 0.52,Rf₆₇ = 0.30, Rf_(101A) = 0.50. [α]_(D) ²⁰ = +166° ± 1° (c = 0.924 indimethylsulphoxide). ED₅₀ = 35.

EXAMPLE 2

7-[D(-)-β-(1,2,3,6-Tetrahydro-2,6-dioxo-4-pyridimidinecarboxamido)-phenylacetamido]-cephalosporanicacid is obtained by reaction of 4.05 g of D(-)-cephaloglycine in 70 mlof methylene chloride with a solution of 3.49 g of orotic acid chloridein 100 ml of absolute tetrahydrofurane in the presence of 2.10 ml oftriethylamine, as in Example 1. The crude product (3.14 g; 58% oftheory) is purified by crystallisation from a mixture oftetrahydrofurane and ether. Melting point 263°-266° C, withdecomposition.

Thin layer chromatogram on silica gel: Rf_(52A) = 0.31, Rf₁₀₁ = 0.57,Rf₆₇ = 0.28, Rf₁₀₁ = 0.52. ED₅₀ = 100.

EXAMPLE 3

6-[D(-)-α-(2,6-Dichloro-4-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid is obtained according to the process of Example 1 by reaction of6-[D(-)-phenylglycylamino]-penicillanic acid with2,6-dichloro-4-pyrimidinecarboxylic acid chloride in methylenedichloride in the presence of triethylamine. The product, dissolved inethyl acetate, is filtered through silica gel and is precipitated with amixture of ether and petroleum ether. Melting point 151° -155° C(decomposition). [α]_(D) ²⁰ = + 136° ± 1° (c = 1.056 indimethylsulphoxide). Thin layer chromatogram on silica gel: Rf_(52A) =0.77; Rf₆₇ = 0.42; Rf₁₀₁ = 0.36; Rf_(101A) = 0.31.

EXAMPLE 4

6-[D(-)-α-(5-n-Butyl-1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid is obtained according to the process of Example 1 by reaction of6-[D(-)-phenylglycylamino]-penicillanic acid with 5-butylorotic acidchloride in methylene chloride in the presence of triethylamine. Theproduct is precipitated from ethyl acetate solution by means of amixture of ether and petroleum ether. Melting point 177° -180° C(decomposition). [α]_(D) ²⁰ = +150° ± 1° (c = 0.875 indimethylsulphoxide). Thin layer chromatogram on silica gel: Rf_(52A) =0.67; Rf₆₇ = 0.42; Rf₁₀₁ = 0.58; Rf_(101A) = 0.57.

EXAMPLE 5

6-[D(-)-α-(5-Phenyl-1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid is obtained according to the process of Example 1 by reaction of6-[D(-)-phenylglycylamino]-pencillanic acid with 5-phenylorotic acidchloride in methylene chloride in the presence of triethylamine. Theproduct is precipitated from methanol solution by means of ether.Melting point 199° -202° C (decomposition). [α]_(D) ²⁰ = + 111° ± 1° (c= 1.027 in dimethylsulphoxide). Thin layer chromatogram on silica gel:Rf_(52A) = 0.61; Rf₆₇ = 0.35; Rf₁₀₁ = 0.59; Rf_(101A) = 0.57.

EXAMPLE 6

6-[D(-)-α-(2,6-Dimethoxy-4-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid is obtained according to the process of Example 1 by reaction of6-[D(-)-phenylglycylamino]-penicillanic acid with2,6-dimethoxy-4-pyrimidinecarboxylic acid chloride in methylene chloridein the presence of triethylamine. The product, dissolved in ethylacetate, is filtered through silica gel and is precipitated with amixture of ether and petroleum ether. Melting point 150° -153° C(decomposition). [α]_(D) ²⁰ = + 176° ± 1° (c = 0.847 indimethylsulphoxide). Thin layer chromatogram on silica gel: Rf_(52A) =0.68; Rf₆₇ = 0.38; Rf₁₀₁ = 0.57; Rf_(101A) = 0.52.

EXAMPLE 7

6-[D(-)-α-(1-Methyl-1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid is obtained according to the process of Example 1 by reaction of6-[D-(-)-phenylglycylamino]-penicillanic acid with 1-methylorotic acidchloride in a mixture of methylene chloride, tetrahydrofurane anddioxane in the presence of triethylamine. The product is precipitatedfrom ethyl acetate solution by means of petroleum ether. Melting point182° -186° C (decomposition). [α]_(D) ²⁰ = + 167° ± 1° (c = 0.908 indimethylsulphoxide). Thin layer chromatogram on silica gel: Rf_(52A) =0.58; Rf₆₇ = 0.33; Rf₁₀₁ = 0.56; Rf_(101A) = 0.53.

EXAMPLE 8

6-[D(-)-α-(1,2,3,4-Tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid is obtained according to the process of Example 1 by reaction of6-[D(-)-phenylglycylamino]-penicillanic acid with uracil-5-carboxylicacid chloride. The product is precipitated from ethyl acetate solutionby means of petroleum ether. Melting point 205° -210° C (decomposition).[α]_(D) ²⁰ = + 174° ± 1° (c = 0.648 in dimethylsulphoxide). Thin layerchromatogram on silica gel: Rf_(52A) = 0.56; Rf₆₇ = 0.33; Rf₁₀₁ = 0.55;Rf_(101A) = 0.51. ED₅₀ = 70.

EXAMPLE 9

7-[D(-)-α-(1,2,3,4-Tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-cephalosporanicacid is obtained according to the process of Example 1 by reaction of7-[D(-)-phenylglycylamino]-cephalosporanic acid with uracil-5-carboxylicacid chloride. The product is purified by recrystallisation frommethanol. Melting point 300° -305° C (decomposition). In a thin layerchromatogram on silica gel Rf_(52A) = 0.31; Rf₆₇ = 0.26; Rf₁₀₁ = 0.53;Rf_(101A) = 0.50. [α]_(D) ²⁰ = +35° ± 1° (c = 0.985 indimethylsulphoxide). UV-spectrum: λ_(max) = 275 nm (ε = 20,000); λ_(min)= 243 nm (ε = 11,400 (in methanol). ED₅₀ = 30.

EXAMPLE 10

6-[D(-)-α-(5-Chloro-1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-penicillanicacid is obtained according to the process of Example 1 by reaction of6-[D(-)-phenylglycylamino]-penicillanic acid with 5-chloroorotic acidchloride. [α]_(D) ²⁰ = + 153° ± 1° (c = 0.747 in dimethylsulphoxide.Rf_(52A) = 0.66; Rf₆₇ = 0.26; Rf₁₀₁ = 0.55; Rf_(101A) = 0.60.

EXAMPLE 11

7-(1,2,3,6-Tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-cephalosporanicacid is obtained according to the process of Example 1 by reaction of7-aminocephalosporanic acid with orotic acid chloride in a mixture ofmethylene chloride, tetrahydrofurane and acetone in the presence oftriethylamine. The product is precipitated from methanol solution bymeans of a mixture of ether and petroleum ether. Melting point 195°-198° C (decomposition). [α]_(D) ²⁰ = + 161° ± 1° (c = 0.900 indimethylsulphoxide). Thin layer chromatogram on silica gel: Rf_(52A) =0.21; Rf₆₇ = 0.19; Rf₁₀₁ = 0.54; Rf_(101A) = 0.45.

EXAMPLE 12

10.0 g of the sodium salt of3-benzoylthiomethyl-7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-4-carboxylicacid are suspended in 60 ml of pyridine, 60 ml of dioxane and 40 ml of a40% strength aqueous mercury perchlorate solution are then successivelyadded to the suspension and the reaction mixture is vigorously stirredfor 45 minutes at 45° C in a nitrogen atmosphere. Thereafter the darkred solution is cooled to 0° C, 20 ml of thiobenzoic acid are added andthe mixture is stirred for 5 minutes at +10° C and extensivelyconcentrated on a rotary evaporator (high vacuum) at 45° C. The residueis well mixed with 200 ml of water, the insoluble mercury salt isremoved by filtering off through "Celite" and the filter residue isrinsed with 100 ml of water. The filtrate is successively extracted with300 ml of toluene, three times with 200 ml at a time of a (1:1) mixtureof "Amberlite" LA-2 and toluene and finally twice with 300 ml at a timeof toluene. The aqueous phase is extensively concentrated on a rotaryevaporator (high vacuum) at 45° C and7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-3-(1-pyridylmethyl)-ceph-3-em-4-carboxylicacid betaine is precipitated by adding ethanol. 3.4 g of the crudeproduct are suspended in 20 ml of water and dissolved by adding 0.1 Nsodium bicarbonate solution at pH 7.0. The solution is then cooled in anice bath and adjusted to pH 4.5 with 1 N hydrochloric acid whilststirring, whereupon the betaine precipitates. It is filtered off andwashed with a little ice-cold water. Melting point 235° -240° C(decomposition). Thin layer chromatogram on silica gel: Rf_(52A) = 0.10;Rf₆₇ = 0.03; Rf₁₀₁ = 0.35; Rf_(101A) = 0.24. [α]_(D) ²⁰ = -39° ± 1° (c =0.961 in dimethylsulphoxide). UV spectrum in 0.5 N NaHCO₃ : λ_(max) =295 nm (ε= 15,000); λ_(max) = 250 nm (ε = 14,200); λ_(min) = 275 nm (ε =14,150). ED₅₀ = 3.

A part of the above betaine (4.0 g) is dissolved in 100 ml of water, 8.0g of sodium iodide are added to the solution, the mixture is cooled inan ice bath and the pH is adjusted to 2.5 by dropwise addition of 2 Nhydrochloric acid whilst stirring. The7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-3-(1-pyridylmethyl)-ceph-3-em-4-carboxylic acid betaine hydroiodide obtained is filtered offand washed with a little cold water. Melting point 218° -220° C(decomposition). [α]_(d) ²⁰ = -33° ± 1° (c = 0.859 indimethylsulphoxide). UV spectrum: λ_(max) 293 nm/ε = 16,800; λ_(max) =238 nm/ε = 22,000; λ_(min) nm/ε = 14,7000 (in 0.5 N NaHCO₃). ED₅₀ = 10.

The starting material can be manufactured as follows.

A solution of 16.0 g of the sodium salt of7-[D(-)-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-cephalosporanicacid in 200 ml of water is added to a solution of 13.8 g of thiobenzoicacid and 8.4 g of sodium bicarbonate in 100 ml of water and the mixtureis stirred for 20 hours at 50° C in a nitrogen atmosphere. The viscousreaction mixture is then cooled to +5° C, covered with ethyl acetate andadjusted to pH 2.5 by adding 20% strength phosphoric acid, and theaqueous phase is repeatedly extracted with ethyl acetate. The extractsare combined, washed with sodium carbonate solution and dried oversodium sulphate, and the solvent is evaporated off on a rotaryevaporator at 40° C. The oil which remains is mixed with a large amountof ether, whereupon solid3-benzoylthiomethyl-7-[D(-)-α-(1,2,3,4tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-4-carboxylicacid is obtained. Melting point 208° -210° C (decomposition).

UV spectrum: λ_(max) 290 nm/ε =23,400; λ_(max) 243 nm/ε = 21,400;λ_(min) 260 nm/ε = 15,900 (in 0.5 N NaHCO₃). Thin layer chromatogram onsilica gel: Rf_(52A) = 0.48; Rf₆₇ = 0.32; Rf₁₀₁ = 0.59; Rf_(101A) =0.55.

EXAMPLE 13

7-[D(-)-α-(1,2,3,6-Tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenyl-acetamido]-3-(1-pyridylmethyl)-ceph-3-em-4-carboxylicacid betaine is obtained according to the process of Example 12 byreaction of 16.0 g of the sodium salt of3-benzoylthiomethyl-7-[D(-)-α-(1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-4-carboxylicacid with 64 ml of a 40% strength aqueous mercury perchlorate solutionin a mixture of 96 ml of pyridine and 96 ml of dioxane. Melting point285° -290° C (decomposition). Thin layer chromatogram on silica gel:Rf_(52A) = 0.05; Rf₁₀₁ = 0.34; Rf_(101A) = 0.24. [α]_(D) ²⁰ = -24° ± 1°(c = 1.050 in dimethylsulphoxide). UV spectrum in 0.5 N NaHCO₃ : λ_(max)= 315 nm (ε = 6,500); λ_(max) = 260 nm (ε = 11,900); λ_(min) = 295 nm (ε= 6,000). ED₅₀ = 10.

7-D(-)-α-(1,2,3,6-Tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-3-(1-pyridylmethyl)-ceph-3-em-4-carboxylicacid betaine hydroiodide melts at 251° -253° C with decomposition. UVspectrum: λ_(max) 315 nm/ε = 7,650; λ_(max) 260/ε = 16,000; λ_(max) 240nm/ε = 16,000; λ_(min) 295 nm/ε = 6,600; λ_(min) 250 nm/ε = 15,900 (in0.5 N NaHCO₃).

The starting material can be manufactured as follows.

3-Benzoylthiomethyl-7-[D(-)-α-(1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-4-carboxylicacid is obtained according to the process of Example 12 by reaction of asolution of 19.0 g of the sodium salt of7-[D(-)-α-(1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxamido)-phenylacetamido]-cephalosporanicacid in 100 ml of water with a solution of 13.8 g of thiobenzoic acidand 8.4 g of sodium bicarbonate in 100 ml of water. Melting point 225°-229° C (decomposition). UV spectrum: λ_(max) 280 nm/ε = 15,700; λ_(max)248 nm/ε = 15,800; λ_(min) 262 nm/ε0 = 15,300; λ_(min) 315 nm/ε = 7,250(in 0.5 N NaHCO₃). Thin layer chromatogram on silica gel: Rf_(52A) =0.51; Rf₆₇ = 0.35; Rf₁₀₁ = 0.61; Rf_(101A) = 0.52.

EXAMPLE 14

6β-(1,2,3,4-Tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-penicillanicacid is obtained according to the process of Example 1 by reaction of6β-amino-penicillanic acid with uracil-5-carboxylic acid chloride in amixture of methylene chloride, tetrahydrofurane and acetone in thepresence of triethylamine. The product is recrystallised from methanol.Melting point 210° -212° C (decomposition). [α]_(D) ²⁰ = + 107° ± 1° (c= 1.113 in dimethylsulphoxide). Thin layer chromatogram on silica gel:Rf_(52A) = 0.53; Rf₆₇ = 0.27; Rf₁₀₁ = 0.50; Rf_(101A) = 0.44.

EXAMPLE 15

7-[D(-)-α-(1,2,3,4-Tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-3[1-(4-carbamoylpyridiniomethyl)]-ceph-3-em-4-carboxylate is obtainedaccording to the process of Example 12 by reaction of 5.5 g of thesodium salt of3-benzoylthiomethyl-7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-4-carboxylicacid with 22.0 g of isonicotinic acid amide and 40 ml of a 40% strengthaqueous mercury perchlorate solution in a mixture of 80 ml of dioxaneand 20 ml of water. Purification of the crude product: 2.6 g of crudeproduct are suspended in 20 ml of water and dissolved at pH 7.0 byadding 0.1 N sodium bicarbonate solution, and the solution is cooled inan ice bath and adjusted to pH 3.0 with 1 N hydrochloric acid whilststirring, whereupon the betaine precipitates. It is filtered off andwashed with a little ice-cold water. Melting point 198° -200° C(decomposition). [α]_(D) ²⁰ = -45° ± 1° (c = 1.035 indimethylsulphoxide). Thin layer chromatogram on silica gel: Rf_(52A) :0.13; Rf₆₇ = 0.10; Rf₁₀₁ = 0.38; Rf_(101A) = 0.42. UV spectrum in 0.5 NNaHCO₃ : λ_(max) = 290 nm (ε = 16,500) and λ_(flat) = 250-260 nm (ε =15,500).

The following compounds can be obtained analogously:7-[D(-)-α-(1,2,3,4-Tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-3-[1-(4-methylpyridiniomethyl)]-ceph-3-em-4-carboxylateby reaction of the sodium salt of3-benzoylthiomethyl-7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-ceph-3-em-4-carboxylicacid with 4-methylpyridine;7[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-3-[1-4-ethylpyridiniomethyl)]-ceph-3-em-4-carboxylateby reaction of the same starting material with 4-ethylpyridine;7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-3-[1-(4-chloropyridiniomethyl)]-ceph-3-em-4-carboxylateby reaction of the same starting material with 4-chloropyridine;7-[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidnecarboxamido)-phenylacetamido]-3-[1-(4-carboxypyridiniomethyl)]-ceph-3-em-4-carboxylateby reaction of the same starting material with isonicotinic acid;7[D(-)-α-(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamido)-phenylacetamido]-3-[1-(3-hydroxypyridiniomethyl)]-ceph-3-em-4-carboxylateby reaction of the same starting material with 3-hydroxypyridine.

EXAMPLE 16

2.72 g of 7-amino-cephalosporanic acid are suspended in 30 ml of a (1:1)mixture of methylene chloride and tetrahydrofurane and 2.10 ml oftriethylamine are added at room temperature whilst stirring, whereupon aclear brown solution is produced. The solution is then cooled to 0° C inan ice bath, a solution of 2.30 g ofD(-)-α-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamido)-phenylacetylchloride (manufactured by reaction ofD(-)-α-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidincarboxamido)-phenylaceticacid with thionyl chloride in tetrahydrofurane) in 70 ml oftetrahydrofurane is added dropwise over the course of 20 minutes at 0° Cto +5° C, whilst stirring and cooling in an ice-bath, and the mixture isthen stirred for 90 minutes at 0° C. 70 ml of phosphate buffer solutionof pH 7.5 are then added to the reaction mixture, which is worked up asin Example 1. The product is identical with 7-[D(-)-α-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxamido)-phenylacetamido]-cephalosporanicacid obtained according to the process of Example 9.

We claim:
 1. A compound of the formula I ##STR11## wherein the grouping-S-A- represents a radical of the formula Ib ##STR12## wherein R₃denotes a carboxyl group andR₄ represents hydrogen, methyl, loweralkanoyloxymethyl, benzoylthiomethyl, pyridiniummethyl,1-oxidized-2-pyridylthiomethyl, or pyridiniummethyl or1-oxidized-2-pyridylthiomethyl substituted by lower alkyl, hydroxy,chloro, carboxy or carbamoyl, and wherein, if the radicals R₁ and R₂ areseparate, R₁ is hydrogen and R₂ is phenyl, thienyl or furyl and, if theradicals R₁ and R₂ are linked, they form, together with the carbon atom,cycloalkyl ring with 4 to 7 carbon atoms, and wherein m represents 0 or1, n represents 1 and B represents2,4-dioxo-1,2,3,4-tetrahydro-pyrimidyl,2,6-dioxo-1,2,3,6-tetrahydro-pyrimidyl, 2,4-dihydroxy-pyrimidyl,2,6-dihydroxy-pyrimidyl, 2,6-dithioxo-1,2,3,6-tetrahydro-pyrimidyl, 2,6dimethoxy-pyrimidyl, 2,6-dichloropyrimidyl,2-methylthio-6-chloro-pyrimidyl, 2-methylthio-6-hydroxypyrimidyl,2,6-bis-morpholino-4-pyrimidyl, and therapeutically acceptable alkali,alkaline earth metal, ammonium and inner salts thereof.
 2. Compounds ofthe formula I as claimed in claim 1, wherein -S-A- represents a radicalof the formula Ib ##STR13## wherein R₃ denotes a free carboxyl group andR₄ denotes a member selected from the group consisting of methyl,acetoxymethyl, benzoylthiomethyl, 1-oxidized-2-pyridylthiomethyl, or1-oxidized-2-pyridylthiomethyl substituted by lower alkyl, hydroxy,chloro, carboxy or carbamoyl and wherein n = 1 andm = 0, R₁ representshydrogen, R₂ represents phenyl, thienyl(2) or furyl(2) and B has themeaning indicated in claim 1, and therapeutically acceptable alkali,alkaline earth metal, ammonium and inner salts thereof.
 3. Compounds ofthe formula I as claimed in claim 1, wherein -S-A- represents a radicalof the formula Ib ##STR14## wherein R₃ denotes a carboxyl group and R₄denotes pyridiniummethyl or pyridiniummethyl substituted by lower alkyl,hydroxy, chloro, carboxy or carbamoyl and wherein n = 1 and m = 0, R₁represents hydrogen, R₂ represents phenyl, thienyl(2) or furyl(2) and Bhas the meaning indicated in claim 1, and therapeutically acceptablealkali, alkaline earth metal, ammonium and inner salts thereof. 4.Compounds of the formula I as claimed in claim 1, wherein -S-A-represents a radical of the formula Ib, wherein R₃ denotes a freecarboxyl group and R₄ denotes a methyl, methoxy, acetoxymethyl,pyridiniummethyl or pyridiniummethyl substituted by lower alkyl,hydroxy, chloro, carboxy, or carbamoyl, and n = 1, m = 0, R₁ representshydrogen and R₂ represents phenyl and B has the meaning indicated inclaim 1, and therapeutically acceptable alkali, alkaline earth metal,ammonium and inner salts thereof.
 5. Compounds of the formula I asclaimed in claim 1, wherein -S-A- represents a radical of the formulaIb, wherein R₃ denotes a carboxyl group and R₄ denotes a methyl,methoxy, acetoxymethyl, benzoylthiomethyl, pyridiniummethyl,1-oxidized-2-pyridylthiomethyl or pyridiniummethyl or1-oxidized-2-pyridylthiomethyl substituted by lower alkyl, hydroxy,chloro, carboxy or carbamoyl, n = 1, m = 0, R₁ represents hydrogen andR₂ represents phenyl and B denotes1,2,3,6-tetrahydro-2,6-dioxopyrimidyl(4) or1,2,3,4-tetrahydro-2,4-dioxopyrimidyl(5), and therapeutically acceptablealkali, alkaline earth metal, ammonium and inner salts thereof.
 6. Acompound as claimed in claim 1, which is7-[D(-)-α-1,2,3,6-tetrahydro-2,6dioxo-4-pyrimidine-carboxamido)-phenylacetamido]-cephalosporanicacid or a therapeutically acceptable alkali earth metal, ammonium orinner salt thereof.
 7. A compound as claimed in claim 1, which is7-[d(-)-α-1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidine-carboxamido)-penylacetamido-cephalosporanic acid or a therapeutically acceptable alkali, alkalineearth metal, ammonium or inner salt thereof.
 8. A compound as claimed inclaim 1, which is7-[D(-)-α-1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidine-carboxamido)-phenylacetamido]-3-(1-pyridylmethyl)-ceph-3-em-4-carboxylicacid in the form of the betaine or a therapeutically acceptable alkali,alkaline earth metal or ammonium salt thereof.
 9. A compound as claimedin claim 1, which is7-]D(-)-α-1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidine-carboxamido)-phenylacetamido]-3-(1-pyridylmethyl)-ceph-3-em-4-carboxylicacid in the form of the betaine or a therapeutically acceptable alkali,alkaline earth metal or ammonium salt thereof.
 10. A compound as claimedin claim 1, which is7-[D(-)-α-1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidine-carboxamido)-phenylacetamido]-3-[1-(4-carbamoylpyridiniomethyl)]-ceph-3-em-4-carboxylicacid in the form of the betaine or a therapeutically alkali, alkalineearth metal or ammonium salt thereof.
 11. An antibacterialpharmaceutical preparation which contains a therapeutically effectiveamount of a compound as claimed in claim 1 or a therapeuticallyacceptable alkali, alkaline earth metal, ammonium or inner salt thereofand a pharmaceutically acceptable excipient.